Modeling, synthesis, and biological evaluation of potential retinoid X receptor (RXR) selective agonists: Novel analogues of 4-[1-(3,5,5,8,8- Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl) -4-hydroxyphenyl)acrylic acid (CD3254)

Peter Jurutka, Ichiro Kaneko, Joanna Yang, Jaskaran S. Bhogal, Johnathon C. Swierski, Christa R. Tabacaru, Luis A. Montano, Chanh C. Huynh, Rabia A. Jama, Ryan D. Mahelona, Joseph T. Sarnowski, Lisa M. Marcus, Alexis Quezada, Brittney Lemming, Maria A. Tedesco, Audra J. Fischer, Said A. Mohamed, Joseph W. Ziller, Ning Ma, Geoffrey M. GrayArjan Van Der Vaart, Pamela Marshall, Carl Wagner

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Three unreported analogues of 4-[1-(3,5,5,8,8-pentamethyl-5-6-7-8- tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), otherwise known as bexarotene, as well as four novel analogues of (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6- pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic acid (CD3254), are described and evaluated for their retinoid X receptor (RXR) selective agonism. Compound 1 has FDA approval as a treatment for cutaneous T-cell lymphoma (CTCL), although treatment with 1 can elicit side-effects by disrupting other RXR-heterodimer receptor pathways. Of the seven modeled novel compounds, all analogues stimulate RXR-regulated transcription in mammalian 2 hybrid and RXRE-mediated assays, possess comparable or elevated biological activity based on EC50 profiles, and retain similar or improved apoptotic activity in CTCL assays compared to 1. All novel compounds demonstrate selectivity for RXR and minimal crossover onto the retinoic acid receptor (RAR) compared to all-trans-retinoic acid, with select analogues also reducing inhibition of other RXR-dependent pathways (e.g., VDR-RXR). Our results demonstrate that further improvements in biological potency and selectivity of bexarotene can be achieved through rational drug design.

Original languageEnglish (US)
Pages (from-to)8432-8454
Number of pages23
JournalJournal of Medicinal Chemistry
Volume56
Issue number21
DOIs
StatePublished - Nov 14 2013

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Jurutka, P., Kaneko, I., Yang, J., Bhogal, J. S., Swierski, J. C., Tabacaru, C. R., Montano, L. A., Huynh, C. C., Jama, R. A., Mahelona, R. D., Sarnowski, J. T., Marcus, L. M., Quezada, A., Lemming, B., Tedesco, M. A., Fischer, A. J., Mohamed, S. A., Ziller, J. W., Ma, N., ... Wagner, C. (2013). Modeling, synthesis, and biological evaluation of potential retinoid X receptor (RXR) selective agonists: Novel analogues of 4-[1-(3,5,5,8,8- Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl) -4-hydroxyphenyl)acrylic acid (CD3254). Journal of Medicinal Chemistry, 56(21), 8432-8454. https://doi.org/10.1021/jm4008517